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| ID | Type | Description | Link |
|---|---|---|---|
| 5R00NS060766 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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This study will test the effects of a medication called tolcapone on cognitive, behavioral, and language problems seen in patients with frontotemporal dementia (FTD). Tolcapone increases the amount of dopamine, a brain chemical that may be lowered in FTD. The study will see if tolcapone can improve thinking, behavior, and language in people with FTD and will look at the effects of the drug on brain activity.
Patients with FTD who are between 40 and 85 years of age may be eligible for this study.
Participants will be seen as outpatients at the Columbia University Medical Center approximately one a week for 4 weeks. They take tolcapone or a placebo (a look-alike pill with no active ingredient) during study week 1. During study week 3, those who took placebo during week 1 now take tolcapone for 1 week and those who took tolcapone now take placebo. In addition, patients undergo the following tests and procedures:
FTD is a significant cause of disability and death with an estimated prevalence of 15 cases per 100,000 persons in the 45- to 64-year-old age range. Despite the magnitude of this problem, there is currently a relative lack of understanding of the causes of, and treatments for, FTD, possibly because criteria for its diagnosis have only recently been developed. As an outcome of the proposed investigations, the investigators expect to determine the effects of cortical dopamine augmentation in FTD, evaluate the effect of dopamine augmentation on processing efficiency with fMRI, and explore the effects of a genetic polymorphism on symptom presentation and disease course. The research proposed in this protocol is significant because it could provide a new class of treatments for FTD, identify the fMRI findings associated with symptom improvement, and determine the contribution of a genetic polymorphism to symptom presentation and disease course.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo then Tolcapone | Placebo Comparator | Participants take placebo during study week 1 and then tolcapone during week 3. On Day 1, 100 mg of tolcapone/placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone/placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone/placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone/placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14. |
|
| Tolcapone then Placebo | Experimental | Participants take tolcapone during study week 1 and then placebo during week 3. On Day 1, 100 mg of tolcapone/placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone/placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone/placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone/placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tolcapone | Drug | 200 mg by mouth three times a day |
|
| Measure | Description | Time Frame |
|---|---|---|
| Reaction Time on the N-back Cognitive Test (0-back Condition) | In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen "N" numbers previously. In the 0-back condition, the subjects are instructed to press the button with the number on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images. | First intervention: Day 8 and Second intervention: Day 21 |
| Reaction Time on the N-back Cognitive Test (1-back Condition) | In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen "N" numbers previously. In the 1-back condition, the subjects are instructed to report the number presented one number back from the number displayed on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images. | First intervention: Day 8 and Second intervention: Day 21 |
| Measure | Description | Time Frame |
|---|---|---|
| Score on Neuropsychiatric Inventory Questionnaire (NPI-Q) | The NPI-Q is a retrospective caregiver/informant-based interview that assesses 12 neuropsychiatric symptom domains including delusions, hallucinations, agitation/aggression, depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, night-time behavioral disturbances and appetite/eating disturbances. Each symptom within a domain are rated by the caregiver in terms of severity (1=mild to 3=severe). Total scores are calculated by adding the composite scores to obtain a score ranging from 0 (no symptoms, better outcome) to 36. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Edward Huey, MD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Irving Medical Center | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9708959 | Background | Adler CH, Singer C, O'Brien C, Hauser RA, Lew MF, Marek KL, Dorflinger E, Pedder S, Deptula D, Yoo K. Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III. Arch Neurol. 1998 Aug;55(8):1089-95. doi: 10.1001/archneur.55.8.1089. | |
| 17063156 | Background | Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007 May;32(5):1011-20. doi: 10.1038/sj.npp.1301227. Epub 2006 Oct 25. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Then Tolcapone | Participants take placebo during study week 1 and then tolcapone during week 3. On Day 1, 100 mg of placebo will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of placebo will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of placebo will be taken only in the morning and afternoon. On Day 8, 200 mg of placebo will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14. |
| FG001 | Tolcapone Then Placebo | Participants take tolcapone during study week 1 and then placebo during week 3. On Day 1, 100 mg of tolcapone will be taken at three specific times: once in the morning, once in the afternoon, once at night. Then, from Days 2-6, 200 mg of tolcapone will be taken three times a day: once in the morning, once in the afternoon, once at night. On Day 7, 200 mg of tolcapone will be taken only in the morning and afternoon. On Day 8, 200 mg of tolcapone will be taken only in the morning. After the last dose on Day 8 is taken, the wash-out period begins and lasts through Day 14. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (Day 1 to Day 8) |
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| Washout (Day 9 to Day 14) |
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| Second Intervention (Day 15 to Day 24) |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Includes all participants who participated in the study since all participants received both tolcapone and placebo in this cross-over designed study. Participants were randomly assigned to start on tolcapone or placebo and then crossed over to received the alternative treatment after a wash-out period. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Reaction Time on the N-back Cognitive Test (0-back Condition) | In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen "N" numbers previously. In the 0-back condition, the subjects are instructed to press the button with the number on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images. | Posted | Mean | Standard Deviation | milliseconds | First intervention: Day 8 and Second intervention: Day 21 |
|
Up to 3 years to track any events during study participation.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Participants | Adverse events data were not collected per Arm, therefore adverse events cannot be reported per Arm. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Elevated liver enzymes | Hepatobiliary disorders | Non-systematic Assessment |
A modified and simplified version of the N-back task was used because patients with FTD were incapable of performing the original version. Another limitation was the relatively brief duration of treatment conditions and washout.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Edward D. Huey, MD | Columbia University | 212-305-1134 | edh2126@cumc.columbia.edu |
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| ID | Term |
|---|---|
| D057174 | Frontotemporal Lobar Degeneration |
| D057180 | Frontotemporal Dementia |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000077867 | Tolcapone |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D001577 | Benzophenones |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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| Placebo | Drug | 200 mg by mouth three times a day |
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| First intervention: Day 8 and Second intervention: Day 21 |
| Score on the Repeated Battery for the Assessment of Neurological Status (RBANS) for Dementia | The RBANS is a brief, individually administered test that captures multiple cognitive domains, including attention, language, visuospatial/constructional abilities, immediate memory, and delayed memory. Index scores range from 0 to 20 (better outcome) for each of the 5 domains tested and the composite scores are added to generated a total index score, which ranges from 0 to 100 (better outcome). | First intervention: Day 8 and Second intervention: Day 21 |
| Score on the Clinical Global Impressions (CGI) Scale | The CGI is often used in treatment studies as a proxy for global functioning and is a subjective score assigned by the treating physician that incorporates elements of illness severity, patient distress, patient impairment, and functioning. The CGI is given a numerical ranking each visit after the first, with 6=major worsening, 5=mild worsening, 4=no change, 3=mild improvement, and 2=major improvement. Scores range from a 2 (better outcome) to a 6 (worse outcome). | First intervention: Day 8 and Second intervention: Day 21 |
| 16862116 | Background | Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9. doi: 10.1038/nature05016. Epub 2006 Jul 16. |
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| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Reaction Time on the N-back Cognitive Test | Mean | Standard Deviation | milliseconds |
|
| OG001 | Tolcapone | Participants take 100 mg of the tolcapone orally three times a day during the first day and then 200 mg orally for the next six days. On the seventh day, participants take 200 mg tolcapone twice a day. On the eighth day, particpants take 200 mg tolcapone once. |
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| Primary | Reaction Time on the N-back Cognitive Test (1-back Condition) | In the N-back task, subjects are given a response pad with response buttons numbered 1, 2, 3, and 4 at the points of a diamond-shaped box and shown a random series of numbers from 1 to 4 appearing for 500 ms every 1.8 seconds at locations corresponding to the positions of the numbers on the response pad. Instructions presented on the screen above the diamond instruct patients to recall the stimulus seen "N" numbers previously. In the 1-back condition, the subjects are instructed to report the number presented one number back from the number displayed on the screen. Three blocks of 40 images will be administered during the working memory task for a total of 120 images. | Posted | Mean | Standard Deviation | milliseconds | First intervention: Day 8 and Second intervention: Day 21 |
|
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|
| Secondary | Score on Neuropsychiatric Inventory Questionnaire (NPI-Q) | The NPI-Q is a retrospective caregiver/informant-based interview that assesses 12 neuropsychiatric symptom domains including delusions, hallucinations, agitation/aggression, depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, night-time behavioral disturbances and appetite/eating disturbances. Each symptom within a domain are rated by the caregiver in terms of severity (1=mild to 3=severe). Total scores are calculated by adding the composite scores to obtain a score ranging from 0 (no symptoms, better outcome) to 36. | Posted | Mean | Standard Deviation | score on a scale | First intervention: Day 8 and Second intervention: Day 21 |
|
|
|
| Secondary | Score on the Repeated Battery for the Assessment of Neurological Status (RBANS) for Dementia | The RBANS is a brief, individually administered test that captures multiple cognitive domains, including attention, language, visuospatial/constructional abilities, immediate memory, and delayed memory. Index scores range from 0 to 20 (better outcome) for each of the 5 domains tested and the composite scores are added to generated a total index score, which ranges from 0 to 100 (better outcome). | Posted | Mean | Standard Deviation | score on a scale | First intervention: Day 8 and Second intervention: Day 21 |
|
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|
| Secondary | Score on the Clinical Global Impressions (CGI) Scale | The CGI is often used in treatment studies as a proxy for global functioning and is a subjective score assigned by the treating physician that incorporates elements of illness severity, patient distress, patient impairment, and functioning. The CGI is given a numerical ranking each visit after the first, with 6=major worsening, 5=mild worsening, 4=no change, 3=mild improvement, and 2=major improvement. Scores range from a 2 (better outcome) to a 6 (worse outcome). | Posted | Mean | Standard Deviation | score on a scale | First intervention: Day 8 and Second intervention: Day 21 |
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|
| 0 |
| 28 |
| 0 |
| 28 |
| 6 |
| 28 |
| Nausea | General disorders | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
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| Headache | General disorders | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
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| Upset Stomach | Gastrointestinal disorders | Non-systematic Assessment |
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| Hyperactive Bowel Syndrome | Gastrointestinal disorders | Non-systematic Assessment |
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| Moderate fall | Injury, poisoning and procedural complications | Non-systematic Assessment |
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| D057177 |
| TDP-43 Proteinopathies |
| D019636 | Neurodegenerative Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D009596 | Nitrophenols |
| D010636 | Phenols |
| D007659 | Ketones |
| D009574 | Nitro Compounds |
| D002241 | Carbohydrates |